The immune system, once triggered by a foreign organism, responds by generating a series of molecules, including molecules known as antibodies, which facilitate the destruction of the foreign organism. Autoimmune diseases are a group of disorders characterised by the failure of the immune system to distinguish between foreign and healthy tissue within the body. The immune system then generates antibodies to healthy or normal tissue including bones and joints (rheumatoid arthritis), platelets (immune thrombocytopenia purpura and blood vessels/connective tissue (systemic lupus erythematosus).
Although the trigger for autoimmune diseases is not completely understood, treatments have been developed that inhibit or halt the severity of the damage done to healthy tissue.
Antibodies produced by people suffering autoimmune diseases bind to healthy tissue resulting in formation of ‘immune complexes’. These immune complexes bind to receptors on the surface of inflammatory white blood cells, called Fc receptors (FcR). When the immune complex binds to the FcR, white blood cells are activated releasing a series of chemicals known as cytokines into the blood system. These chemicals lead to the destruction of tissue and joints and also propagates the immune response so that attack on healthy tissue continues.
Traditional treatments, such as those for rheumatoid arthritis, include the use of cytotoxic agents such as methotrexate. Methotrexate non-specifically kills all dividing cells, eliminating the cells producing the antibodies. The major side effect of methotrexate is that it non-specifically kills cells of the immune system leaving the patient immuno-supressed. More recently, a number of new products have been launched which inhibit the naturally produced chemicals that lead to tissue/joint destruction. The limitation of some of these products is that they target only one of the many inflammatory chemicals released. For example, Enbrel and Remicade inhibit the action of Tumour Necrosis Factor alpha (TNF) whilst Kineret inhibits Interleukin-1.
It would be understood by the person skilled in the art that although the above discussion principally concerns rheumatoid arthritis, the scope of the present invention is not so limited and the scope extends to other autoimmune diseases such as immune thrombocytopenia purpura, systemic lupus erythematosus and Crohn's disease.
The Fc receptor is a useful target for drug development because it is upstream in the inflammatory process and in theory, preventing the triggering of this receptor should block the release of many of the tissue-damaging chemicals.
FcRs consist of a family of highly related receptors that are specific for the Fc portion of immunoglobulin (Ig). Receptors have been defined for each of the immunoglobulin classes and as such are defined by the class of Ig to which they bind (e.g. Fc gamma receptors (FcγR) bind gamma immunoglobulin (IgG), Fc epsilon receptors (FcεR) bind epsilon immunoglobulin (IgE), Fc alpha receptors (FcαR) bind alpha immunoglobulin (IgA)). Among the FcγR receptors, three sub-family members have been defined; FcγRI, which is a high affinity receptor for IgG; FcγRII, which are low affinity receptors for IgG that bind to aggregates of immune complexes; and FcγRIII, which are low affinity receptors that bind to immune complexes. In recent times, further differentiation of these receptors has been achieved, such as, for example the identification of FcγRIIa.
These receptors are highly related structurally but perform different functions. The structure and function of FcγRII is of interest because of its interaction with immune complexes and its association with disease.
FcγR are expressed on most hematopoietic cells, and through the binding of IgG plays a key role in homeostasis of the immune system and host protection against infection. FcγRII essentially binds only to IgG immune complexes and is expressed on a variety of cell types including, for example, monocytes, macrophages, neturophils, eosinophils, platelets and B lymphocytes. FcγRII is involved in various immune and inflammatory responses including antibody-dependent cell mediated cytotoxicity, clearance of immune complexes, release of inflammatory mediators and regulation of antibody production. The binding of IgG to a FcγR can lead to disease indications that involve regulation by FcγR. For example, thrombocytopenia purpura involves platelet damage resulting from FcγR-dependent IgG immune complex activation of platelets or their destruction by FcγR+ phagocytes. In addition, various inflammatory diseases including rheumatioid arthritis, and systemic lupus erythematosus involve IgG immune complexes.
FcγRs exist at the surface of a cell. In essence, they are dimers of two virtually identical structures which meet in such as way that they define a groove. Structures of these dimers are disclosed in International Patent Application No. WO 99/40117. The Fc portion of aggregated antibody binds to this groove, hence compounds designed to interfere with the binding in the groove may inhibit antibody/receptor binding.
Potentially suitable compounds are derived from random screening as well as rational drug design to modulate Fc receptors. Drug design depends at least in part on the structure of the site to which the compounds are intended to bind. U.S. Pat. No. 6,355,683 has postulated the structure of the binding region of FcγRIIa binding region based on X-ray crystallographic analysis. It is believed that the relevant binding site (that is, the groove) has a lip comprising lysine and histidine residues and represents a target for interaction with hydrogen-bonding and/or acidic groups in a suitable modulator. The wall of the groove contains a phenylalanine benzene ring and may be a target for a hydrophobic interaction, particularly π-π interactions. The ‘floor’ of the groove includes Phe121, Thr152, Leu159 and Ser161 and together with Asn154, Lys117 (backbone carbonyl) and Thr 119. These proteins are believed to be arranged to form a pocket that is capable of strong hydrogen bonding and/or Van der Waals interactions with a modulator or a ligand.
Because FcRs are involved in a variety of biological mechanisms, it is important that the compounds identified as suitable for affecting the binding of immunoglobulins to FcγR do not adversely affect the other biological functions of FcRs. For example, U.S. Pat. No. 6,355,683 discloses certain classes of aromatic, cyclic and amino acid species that modulate binding of immunoglobulins to Fc receptors.
While many hundreds of species have been identified which affect the binding of immunoglobulins to FcR, their binding affinity and suitability for use in drug formulations varies. Accordingly there is an ongoing need for identification of potential new chemical species that can be used in pharmaceutical compositions for modulation of binding of immunoglobulins to Fc receptors.